Disorders of mucus clearance (mucous stasis) and increased mucous production are common problems that impact a variety of human conditions. This is true even in the setting of normal epithelial function and a normally functioning cellular mucociliary clearance apparatus whereupon mucociliary clearance is suboptimal for the particular condition. A number of diseases and/or conditions may lead to suboptimal mucous clearance and/or excess mucous production. In such situations, mucociliary clearance may be considered impaired even though no defects or abnormalities exist in the cellular mucociliary clearance apparatus as the normal functioning cellular mucociliary apparatus is not sufficient given the underlying condition of the patient.
For example, individuals with neuromuscular weakness caused by congenital or genetic conditions, such as, but not limited to, muscular dystrophy, spinal muscular atrophy, and ALS, suffer from recurrent pneumonia due to poor cough clearance which leads to mucous stasis. In addition, individuals with acquired anatomic problems resulting in muscular weakness, such as but not limited to, paraplegia, quadriplegia, diaphragmatic paralysis and the like, suffer the same fate. Other subjects, such as those suffering from excess mucous production due to conditions such as, but not limited to, asthma and status asthmaticus, those suffering from impaired immunity due to conditions such as, but not limited to, immunoglobulin deficiency, SCID, hyper-IgE syndrome, and similar conditions, those suffering from anatomic respiratory abnormalities impairing mucus clearance, and those suffering from recurrent pneumonia for unclear causes and those suffering from oropharyngeal abnormalities, suffer from atelectasis and/or pneumonia due to excess mucus production that overwhelms the capacity of the mucociliary clearance apparatus to transport it effectively. These disorders due to or resulting in suboptimal mucous clearance and/or excess mucous production are a serious recurrent problem causing considerable morbidity and are also a contributing cause to mortality. Thus even in diseases where mucociliary clearance is normal, enhancement of mucociliary clearance to supernormal levels is beneficial to combat particular diseases.
The art is lacking compounds and treatment methods to augment mucociliary clearance and/or airway epithelial cell function. The art is particularly lacking compounds and treatment methods to enhance mucociliary clearance and/or airway epithelial cell function in subjects that do not have a congenital or genetic defect in the cellular mucociliary clearance apparatus and/or an acquired abnormality in the cellular mucociliary clearance apparatus. Such compounds and treatment methods would offer substantial benefits to those subjects by treating conditions arising from suboptimal mucous clearance and/or excess mucous production and similar conditions.
The present disclosure provides a solution to the problems encountered in the art by providing compounds and treatment methods to enhance mucociliary clearance and/or airway epithelial cell function to overcome suboptimal mucous clearance and/or excess mucous production. In addition, the present disclosure provides a solution to the problems encountered in the art by providing compounds and treatment methods to induce supra-normal mucociliary clearance to enhance mucociliary clearance and/or airway epithelial cell function to overcome suboptimal mucous clearance and/or excess mucous production. Furthermore, the present disclosure provides the foregoing benefits in a subject wherein the subject is free from a congenital or genetic defect in the cellular mucociliary clearance apparatus and/or an acquired abnormality in the cellular mucociliary clearance apparatus. In one embodiment, the suboptimal mucous clearance and/or increased mucous production is due to or associated with neuromuscular diseases, anatomic respiratory abnormalities, acquired anatomic problems resulting in muscular weakness, anatomic weakness, asthma and status asthmaticus, relative susceptibility to respiratory infection (such as due to impaired immunity), and/or excess mucous production.